A 38-year-old woman presents with bilateral breast cancer diagnosed 6 months apart. Family history reveals her mother had breast cancer at age 42 and her sister had ovarian cancer at age 35. Which investigation is most appropriate to confirm the suspected hereditary cancer syndrome?

Question

Accepted Answer

B. BRCA1/BRCA2 gene sequencing. ## Investigation of Choice for Hereditary Breast-Ovarian Cancer

**Key Point:** BRCA1/BRCA2 gene sequencing is the gold standard confirmatory test for hereditary breast and ovarian cancer syndrome (HBOC), which accounts for 5–10% of all breast cancers.

### Clinical Presentation Clues
- Bilateral breast cancer
- Early age of onset (before 50 years)
- Multiple affected family members across generations
- Presence of ovarian cancer in the family

These features strongly suggest a germline mutation in BRCA1 or BRCA2.

### Why BRCA Gene Sequencing?

| Feature | BRCA1/BRCA2 Sequencing | Other Tests |
|---------|------------------------|-------------|
| **Diagnostic accuracy** | Identifies pathogenic germline mutations (>95% sensitivity in high-risk families) | Cannot identify genetic predisposition |
| **Inheritance pattern** | Reveals autosomal dominant inheritance | Reflects only current tumor status |
| **Counseling value** | Enables cascade testing in relatives; guides surveillance and prophylaxis | No predictive value for unaffected family members |
| **Therapeutic implications** | PARP inhibitors (olaparib, rucaparib) approved for BRCA-mutant tumors | No direct therapeutic guidance |

**High-Yield:** BRCA1 mutations account for ~45% of hereditary breast cancers; BRCA2 for ~35%. Both confer ~70% lifetime risk of breast cancer and ~40% risk of ovarian cancer.

**Clinical Pearl:** Genetic testing should be offered to:
- Women diagnosed with breast cancer before age 45
- Women with bilateral breast cancer
- Women with breast and ovarian cancer
- Families with multiple affected members
- Ashkenazi Jewish ancestry (founder mutations: 185delAG, 5382insC in BRCA1; 6174delT in BRCA2)

**Mnemonic: BRCA-PARP** — BRCA mutations predict Platinum and PARP inhibitor sensitivity, making molecular diagnosis therapeutically critical.

[cite:Robbins 10e Ch 7]

Answer

A. Serum CA-125 and CEA levels

Answer

C. Mammography and transvaginal ultrasound

Answer

D. Immunohistochemistry for HER2 on tumor tissue

A 38-year-old woman presents with bilateral breast cancer diagnosed 6 months apart. Family history reveals her mother had breast cancer at age 42 and her sister had ovarian cancer at age 35. Which investigation is most appropriate to confirm the suspected hereditary cancer syndrome?

Explanation

Investigation of Choice for Hereditary Breast-Ovarian Cancer

Clinical Presentation Clues

Why BRCA Gene Sequencing?

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Feature	BRCA1/BRCA2 Sequencing	Other Tests
Diagnostic accuracy	Identifies pathogenic germline mutations (>95% sensitivity in high-risk families)	Cannot identify genetic predisposition
Inheritance pattern	Reveals autosomal dominant inheritance	Reflects only current tumor status
Counseling value	Enables cascade testing in relatives; guides surveillance and prophylaxis	No predictive value for unaffected family members
Therapeutic implications	PARP inhibitors (olaparib, rucaparib) approved for BRCA-mutant tumors	No direct therapeutic guidance